Anti‐mitotic agent SB‐216 overcomes taxane resistance in castration‐resistant prostate cancer and exhibits anti‐tumour efficacy in pancreatic cancer

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Abstract Background and Purpose The clinical success of small‐molecule drugs in treating pancreatic and prostate cancer patients has been both promising and challenging. Whereas patients with advanced‐stage tumours have significant initial responses to chemotherapy, many have experienced rapid resistance, metastasis and recurrence after curative‐intent surgery. Traditional tubulin inhibitors are widely used in cancer treatment, but their effectiveness is often limited by drug resistance and toxicity. SB‐216, a novel colchicine‐binding site inhibitor (CBSI), has been reported to demonstrate potential efficacy in overcoming paclitaxel (PTX) resistance in a melanoma xenograft model (A375/TxR) and inhibiting spontaneous metastasis. Experimental Approach We evaluated SB‐216 as a therapeutic option for advanced malignancies, specifically castration‐resistant prostate cancer (CRPC) and pancreatic ductal adenocarcinoma (PDAC). We conducted preclinical evaluations of SB‐216 in CRPC parental and taxane‐resistant lines. Additionally, we investigated the effects of SB‐216 on PDAC cells, xenograft models and patient‐derived models. Key Results In vitro, SB‐216 potently induces G2/M phase cell cycle arrest, inhibits cell proliferation, colony formation and cell migration in a concentration‐dependent manner. In vivo, SB‐216 significantly attenuates tumour growth in prostate cancer xenograft models, overcomes PTX resistance and confers a survival benefit at a dose of 2 mg kg −1 without affecting body weight. SB‐216 also inhibits the growth of PDAC xenograft tumours and the growth of patient‐derived cells and organoids. Conclusions and Implications Our findings suggest that SB‐216 is a promising candidate as a new generation of anti‐mitotic agents for advanced cancer, and further exploration in combination with other agents is warranted.

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